The medical repair of bones and joints and other tissue in the human body presents significant difficulties, in part due to the materials involved. Each bone has a hard, compact exterior surrounding a spongy, less dense interior. The long bones of the arms and legs, the thigh bone or femur, have an interior containing bone marrow. The material that bones are mainly composed of is calcium, phosphorus, and the connective tissue substance known as collagen.
Bones meet at joints of several different types. Movement of joints is enhanced by the smooth hyaline cartilage that covers the bone ends, by the synovial membrane that covers the hyaline cartilage and by the synovial fluid located between opposing articulating surfaces.
Cartilage damage produced by disease such as arthritis or trauma is a major cause of physical deformity and dehabilitation. In medicine today, the primary therapy for loss of cartilage is replacement with a prosthetic material, such as silicone for cosmetic repairs, or metal alloys for joint realignment. The use of a prosthesis is commonly associated with the significant loss of underlying tissue and bone without recovery of the full function allowed by the original cartilage. The prosthesis is also a foreign body which may become an irritating presence in the tissues. Other long-term problems associated with the permanent foreign body can include infection, erosion and instability.
The lack of a truly compatible, functional prosthesis subjects individuals who have lost noses or ears due to burns or trauma to additional surgery involving carving a piece of cartilage out of a piece of lower rib to approximate the necessary contours and inserting the cartilage piece into a pocket of skin in the area where the nose or ear is missing.
Surgical removal of infected or malignant tissue is disfiguring and can have harmful physiological and psychological effects. Regeneration of soft tissue, or tissue that mimics the natural properties of the removed tissue, can avoid or lessen these untoward consequences. Finally, a device which delivers a therapy could aid the regeneration of tissue, minimize risk of infection, and/or treat any underlying disease or condition.
The foregoing being exemplary, a device according to the teachings of the present invention is expected to add utility in many areas, see Table 1, which is meant to be expansive of the foregoing, and not limiting.
TABLE 1Examples of tissues and procedures potentiallybenefiting from the teachings of the present inventionBoneBone tissue harvestSpinal arthrodesisSpinal fixation/fusionOsteotomyBone biopsyMaxillofacial reconstructionLong bone fixationCompression fracturesHip reconstruction/replacementKnee reconstruction/replacementHand reconstructionFoot reconstructionAnkle reconstructionWrist reconstructionElbow reconstructionShoulder reconstructionCartilageMosaicplastyMeniscusDentalRidge augmentationThird molar extractionTendonLigamentSkinTopical woundBurn treatmentBiopsyMuscleDuraLungLiverPancreasGall bladderKidneyNervesArteryVeinBypass SurgeryCardiac catheterizationHeartEsophagusMediastinumHeart valve replacementPartial organ removal
In the past, bone has been replaced using actual segments of sterilized bone or bone powder or porous surgical steel seeded with bone cells which were then implanted. In most cases, repair to injuries was made surgically. Patients suffering from degeneration of cartilage had only pain killers and anti-inflammatories for relief.
Until recently, the growth of new cartilage from either transplantation or autologous or allogeneic cartilage has been largely unsuccessful. Consider the example of a lesion extending through the cartilage into the bone within the hip joint. Picture the lesion in the shape of a triangle with its base running parallel to the articular cavity, extending entirely through the hyaline cartilage of the head of the femur, and ending at the apex of the lesion, a full inch (2.54 cm) into the head of the femur bone.
Presently, there is a need to successfully insert an implant device which will assure survival and proper future differentiation of cells after transplantation into the recipient tissue defect. Difficulties have been experienced with engineering the implant environment such that cells may survive, and also with supporting proper cell differentiation.
Presently, for example, cartilage cells, called chondrocytes, when implanted along with bone cells, can degenerate or dedifferentiate into more bone cells. Because hyaline cartilage is an avascular tissue, it should be protected from intimate contact with sources of high oxygen tension such as blood. Bone cells, in contrast, require high oxygen levels and blood. For this reason, the subchondral bone region of the device should be isolated from the cartilage region, at least so far as oxygen and blood are concerned.
Most recently, two different approaches to treating articular lesions have been advanced. One approach such as disclosed in U.S. Pat. No. 5,041,138 is coating bioderesorbable polymer fibers of a structure with chemotactic ground substances. No detached microstructure is used. The other approach such as disclosed in U.S. Pat. No. 5,133,755 uses chemotactic ground substances as a microstructure located in voids of a macrostructure and carried by and separate from the biodegradable polymer forming the macrostructure. Thus, the final spatial relationship of these chemotactic ground substances with respect to the bioresorbable polymeric structure is very different in U.S. Pat. No. 5,041,138 from that taught in U.S. Pat. No. 5,133,755.
The fundamental distinction between these two approaches presents three different design and engineering consequences. First, the relationship of the chemotactic ground substance with the bioresorbable polymeric structure differs between the two approaches. Second, the location of biologic modifiers carried by the device with respect to the device's constituent materials differs. Third, the initial location of the parenchymal cells differs.
Both approaches employ a bioresorbable polymeric structure and use chemotactic ground substances. However, three differences between the two approaches are as follows.
I. Relationship of Chemotactic Ground Substances with the Bioresorbable Polymeric Structure
The design and engineering consequence of coating the polymer fibers with a chemotactic ground substance is that both materials become fused together to form a single unit from structural and spatial points of view. The spaces between the fibers of the polymer structure remain devoid of any material until after the cell culture substances are added.
In contrast, the microstructure approach uses chemotactic ground substances and/or other materials, separate and distinct from the macrostructure. The microstructure resides within the void spaces of the macrostructure. Additionally, an embodiment incorporating a microstructure may use materials such as polysaccharides and chemotactic ground substances that are spacially separate from the macrostructure polymer thereby forming an identifiable microstructure, separate and distinct from the macrostructure polymer.
The design and engineering advantage to having a separate and distinct microstructure capable of carrying other biologically active agents can be appreciated in the medical treatment of articular cartilage. RGD attachment moiety of fibronectin is a desirable substance for attaching chondrocytes cells to the lesion. However, RGD attachment moiety of fibronectin is not, by itself, capable of forming a microstructure of velour in the microstructure approach. Instead, RGD may be blended with a microstructure material prior to investment within macrostructure interstices.
II. Location of Biologic Modifiers Carried by a Device with Respect to the Device's Constituent Materials
Coating only the polymer structure with chemotactic ground substances necessarily means that the location of the chemotactic ground substance is only found on the macrostructure (e.g., bioresorbable polymer) fibers, thereby affording a two dimensional presentation. The microstructure approach uses the microstructure to carry biologic modifiers (e.g., growth factors, morphogens, drugs, etc.), however the presentation is analogous to a three dimensional presentation. Therefore, the coating approach has a limited capacity to carry biologic modifiers with the biodegradable polymeric structure.
III. Initial Location of the Parenchymal Cell
Because the coating approach attaches the chemotactic ground substances to the surfaces of the structure and has no microstructure resident in the void volume of the device, the coating approach precludes the possibility of establishing a network of extracellular matrix material, specifically a microstructure, within the spaces between the fibers of the polymer structure once the device is fully saturated with cell culture medium. The coating approach predetermines that any cells introduced via culture medium will be immediately attracted to the surface of the structure polymer and attach thereto by virtue of the chemotactic ground substances on the polymer's surfaces.
The consequence of confining chemotactic ground substances to only the surfaces of the polymeric structure places severe restrictions on the number of cells that can be accommodated by the coated device.
In contrast with the coating approach, the microstructure approach, by locating chemotactic ground substances in the void spaces of the device, makes available the entire void volume of the device to accommodate the attracted cells which then lay down their own extracellular matrix resulting in a more rapid and complete tissue regrowth or ingrowth.
One of the many objects of this invention, as will be discussed, is to protect and aid cellular ingrowth or regeneration of various types of new tissue, as well as providing methods of concurrent delivery of therapies and other treatments.
Another object of the present invention is the delivery of therapeutic drugs or biologically active agents from a device having the aforementioned macrostructure and microstructure. Such a device could be useful in preventing unwanted effects of various therapies (i.e., interventional surgical procedures, radionuclear therapies, drugs, etc.) For example, early postoperative atrial fibrillation (AF) is common following cardiac surgery, occurring in 25 to 35% of patients after coronary artery bypass grafting (CABG). Postoperative AF following cardiac or lung surgery can cause a number of complications, including congestive heart failure, stroke, and hemodynamic instability. It is responsible for increased hospital costs and prolonged hospitalization. This tachyarrhythmia usually occurs within one week following cardiac or lung surgery and generally resolves over the next three weeks without any long-term risk for recurrence. Previous studies have shown that the peak incidence of early postoperative AF is on the second postoperative day after coronary artery bypass grafting (CABG). Seventy percent of the patients who had AF following CABG experienced this arrhythmia within the first three days postoperatively. Moreover, the incidence of early postoperative AF varies depending on the type of procedure, being highest in patients having valvular surgery with or without CABG. Off-pump CABG has been associated with a lower incidence of AF than traditional on-pump CABG.
The precise etiology of atrial fibrillation is unclear. Some studies have shown that an increased inflammatory response correlates with the occurrence of early postoperative AF. It has been shown that elevated C-reactive protein is associated with the occurrence of AF. It has been reported that anti-inflammatory therapy significantly reduced the incidence of early postoperative AF following cardiac surgery. Yared and colleagues [Yared, Starr, Torres, et al., Effect of Single Dose, Post-induction Dexamethasone on Recovery After Cardiac Surgery, Ann. Thorac. Surg. 69:1420-1424 (2000)] demonstrated that patients receiving corticosteroid therapy had a significantly lower incidence of postoperative AF following both CABG and valvular surgery than patients that did not receive corticosteroid therapy. Matthew and colleagues [Matthew, Fontes, Tudor et al., A Multicenter Risk Index for Atrial Fibrillation After Cardiac Surgery, JAMA 291:1720-1729 (2004)] found that administering non-steroidal anti-inflammatory medication was associated with a reduction in the odds of developing postoperative atrial fibrillation, suggesting that inflammation may contribute to the pathogenesis of postoperative atrial fibrillation.
It has recently been found that systemic delivery of anti-inflammatory medications have reduced the incidence of AF following cardiac surgery. However, there are significant drawbacks of using systemic anti-inflammatory medication following cardiac surgery. For example, non-steroidal anti-inflammatory medication can have detrimental effects on renal function and steroidal anti-inflammatory medication can impair wound healing and reduce the immune response. It is desirable to overcome these limitations of systemic delivery of anti-inflammatory agents by locally delivering them to the desired tissue, namely the heart and great vessels and achieve the desired local tissue concentration while minimizing or limiting exposure of these agents to other tissues within the body. The discovery of the present invention allows local delivery of these types of drugs on a local scale, affording the beneficial effect of the drug on the target site, and further avoiding the drawbacks of delivery on a systemic scale.
Zaffaroni in U.S. Pat. No. 3,948,254 describes an implantable or insertable drug delivery device wherein a drug carrier material is enclosed in a microporous surrounding wall, to provide for extended drug release from the drug carrier material as the drug diffuses through the microporous surrounding wall.
Levy et al. in U.S. Pat. No. 5,387,419 describe a biodegradable implant suitable for localized drug delivery. The implant is prepared as a polymer/solvent and drug coating that polymerizes in situ to form a coating or film that serves to elute the drug.
Altman et al. in U.S. Pat. No. 6,296,630 describe a drug delivery system, wherein a “patch” for drug delivery is applied directly against the heart, wherein the drug to be delivered is renewable by accessing an implanted port in fluid communication with the patch.
Lindemans in U.S. Pat. No. 6,748,653 describes a drug delivery and defibrillator pad, wherein a defibrillator pad having a defibrillating lead is placed against the heart, and the pad is further arranged to deliver a drug to the heart. Lindemans described the pad as being biodegradable.
Cox in U.S. Pat. No. 6,730,016 describes a jacket that may be placed around all or a portion of the heart to constrain the heart from overexpansion. The jacket may have reinforcing ribs to provide structure to the jacket, and the material may be limited in its ability to expand, thereby preventing harm to the organ. The jacket may be capable of localized drug delivery.
Theeuwes in U.S. Pat. No. 6,726,920 describes an implantable patch for drug delivery having an impermeable outside layer and a permeable inside layer, such that a drug reservoir contained between the two layers is arranged to deliver a drug by diffusion through the permeable inside layer.